(a) Field of the Invention
The invention relates to 2-(2,3,5,6-tetrafluoro-4-pyridyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxides, to pharmaceutical compositions containing the same and to the method of use thereof in the treatment of degenerative disease.
(b) Information Disclosure Statement
The inhibition of proteolytic enzymes by nontoxic reagents is useful in the treatment of degenerative disorders, such as emphysema, rheumatoid arthritis and pancreatitis, in which proteolysis is a substantive element.
Protease inhibitors are widely utilized in biomedical research. Serine proteases are the most widely distributed class of proteolytic enzymes. Some serine proteases are characterized as chymotrypsin-like or elastase-like based upon their substrate specificity.
Chymotrypsin and chymotrypsin-like enzymes normally cleave peptide bonds in proteins at a site at which the amino acid residue on the carboxyl side is typically Trp, Tyr, Phe, Met, Leu or another amino acid residue which contains aromatic or large alkyl side chains.
Elastase and elastase-like enzymes normally cleave peptide bonds at a site at which the amino acid residue on the carboxyl side of the bond is typically Ala, Val, Set, Leu or other similar, smaller amino acids.
Both chymotrypsin-like and elastase-like enzymes are found in leukocytes, mast cells and pancreatic juice in higher organisms, and are secreted by many types of bacteria, yeast and parasites.
Cha, Blochem. Pharmacol., 1975, 24, 2177-2185, discusses kinetic approaches to the study of the binding of inhibitors to macromolecules, such as enzymes, and methods for the determination of such parameters as the inhibition constants, reaction rates and bound and unbound enzyme concentrations.
Jones et al. U.S. Pat. No. 4,369,183, issued Jan. 18, 1983 (a divisional of U.S. Pat. No. 4,276,298, issued Jun. 30, 1981, which in turn is a continuation-in-part of Ser. No. 889,762, filed Mar. 24, 1978, now abandoned) disclose compounds of the formula: ##STR2## wherein R is ##STR3## where n is 1 to 5; and X is independently selected from (1) fluoro; (2) nitro; except that where X is only nitro, n must be 2 and X must be 2,4- or 3,5-dinitro; (3) trifluoromethyl; (4) cyano; (5) C.sub.1-3 alkoxycarbonyl; (6) C.sub.1-3 alkylcarbonyl; (7) carboxy; (8) carbamoyl; (9) C.sub.1-3 alkylacylamino; (10) C.sub.1-3 alkylsulfonyl; (11) N,N-di-(C.sub.1-3 alkyl) sulfamyl; (12) trifluoromethoxy; (13) trifluoromethylthio; and (14) trifluoromethylsulfonyl; and (15) trifluoromethylsulfinyl or substituted pyridyl, where m has the same meaning as n above, and Y has the same meaning ##STR4## as X, except that it may additionally be mono-nitro. The compounds are said to have protease enzyme inhibitory activity, especially elastase inhibitory activity, and to be useful in the treatment of emphysema, rheumatoid arthritis and various inflammatory diseases. Specifically disclosed are those compounds wherein R is 2,3,4,5,6-pentafluorophenyl, 3,5-dinitrophenyl, 3-nitropyrid-2-yl, 3- or 5-nitropyrid-2-yl, 5-cyanopyrid-2-yl and 3,5-dinitropyrid-2-yl.
Jones et al. European Patent Application 26791, published Apr. 15, 1981, contains essentially the same disclosure as that shown in U.S. Pat. Nos. 4,369,183 and 4,276,298 which are described hereinabove.
E1-Maghraby et al. Proc. Indian Natl. Sci. Acad., Part A, 1987, 53 (3), 431-440 disclose 6-nitro-2-(4-pyridinyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide and 6-nitro-2-(2-pyridinyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide. No utility is disclosed for these compounds.
Yogi et al. Bull. Chem. Soc. Jpn. 1987, 60, 731-735 disclose 2-(6-benzoyl-2-phenyl-3-pyridinyl)-2-benzisothiazol-3(2H)-one 1,1-dioxide and 2-(6-chloro-2-phenyl-3-pyridinyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide without an indication of utility.
Badawi et al. Oriental J. Chem. 1986, 2(1), 40-44 disclose 6-(2-pyridinylsulfamoyl)-2-(2-pyridinyl)-1,2-benzisothiazol-3-(2H)-one 1,1-dioxide as an amoebicidal agent.
Rabhofer et al. Israel Journal of Chemistry 1979, 18, 249-252 disclose 2-(2,3,5,6-tetrafluoro-4-pyridinyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide without an indication of utility. A similar disclosure can be found in Rabhofer et al., Tetrahedron Lett. 1979, 14, 1217-1218.
Abramovitch et al. J. Org. Chem 1974 39(13), 1795-1801 disclose 2-(2-pyridinyl)-1,2-benzisothiazol-3-(2H)-one 1,1-dioxide without an indication of utility.
Ashe et al. J. Biol. Chem. 1981, 256(22), 11603-11606 disclose a number of N-aryl-1,2-benziosothiazol-3(2H)-one 1,1-dioxides having inhibitory activity against human leukocyte and porcine pancreatic elastase.